Search

Background: The outcome in older patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory due to high relapse and nonrelapse mortality (NRM) rates. Allogeneic stem cell transplantation (alloHSCT) as postremission therapy has an important role in reducing relapse rate, albeit its application is limited in older adult patients due to alloHSCT-related morbidity and mortality. Reduced-intensity conditioning (RIC) alloHSCT has been developed as a less toxic conditioning regimen, but comparative studies with myeloablative conditioning (MAC) are limited in patients with ALL., Methods: In this retrospective study, RIC-alloHSCT (n = 111) was compared with MAC-alloHSCT (n = 77) in patients aged 41 to 65 y with ALL in first complete remission. MAC was predominantly applied by combining high-dose total body irradiation and cyclophosphamide, whereas RIC mainly consisted of fludarabine and 2 Gy total body irradiation., Results: Unadjusted overall survival was 54% (95% confidence interval [CI], 42%-65%) at 5 y in MAC recipients compared with 39% (95% CI, 29%-49%) in RIC recipients. Overall survival and relapse-free survival were not significantly associated with type of conditioning after adjusted for the covariates age, leukemia risk status at diagnosis, donor type, and donor and recipient gender combination. NRM was significantly lower after RIC (subdistribution hazard ratio: 0.41, 95% CI, 0.22-0.78; P  = 0.006), whereas relapse was significantly higher (subdistribution hazard ratio: 3.04, 95% CI, 1.71-5.40; P < 0.001)., Conclusions: Collectively, RIC-alloHSCT has resulted in less NRM, but it was also found to be associated with a significantly higher relapse rate. These results suggest that MAC-alloHSCT may provide a more effective type of consolidation therapy for the reduction of relapse and that RIC-alloHSCT may be restricted to patients at higher risk for NRM., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Tissue injury often occurs as collateral damage after chemotherapy and radiotherapy and is associated with significant comorbidity and mortality. The arsenal of options to prevent tissue injury other than dose reduction is limited, and treatment is mostly aimed at symptom relief and prevention of complications, such as bacterial translocation and malnourishment. Novel approaches directed at prevention and early repair of damaged tissues are highly anticipated., Recent Findings: Innate lymphoid cells (ILC) are important in tissue homeostasis and wound healing. Most knowledge of ILC is based on studies in mice, and the contribution of ILC to repair therapy-induced tissue damage in humans is relatively understudied. A picture is nevertheless emerging, suggesting that ILC have several means to maintain tissue homeostasis. Subsets of ILC produce, for example, interleukin (IL)-22 or amphiregulin (AREG) that induce epithelial tissue repair and the release of microbiome modulating proteins. In addition, ILC have immune-regulatory capacities given that adoptive transfer of ILC in a mouse model of graft versus host disease (GvHD) attenuated tissue inflammation., Summary: ILC are important in tissue maintenance and damage repair and as such have the potential to be developed as (adoptive) therapy to prevent and repair therapy-induced tissue damage.

Background: Acute graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation which causes high morbidity and mortality among patients who do not respond to steroid treatment. Mesenchymal stromal cells (MSCs) have immune modulatory abilities and earned their place in the treatment of GvHD after a pediatric patient remarkably recovered from steroid-refractory acute GvHD with MSC salvage therapy. Large, prospective clinical trials evaluating the potency of MSCs have however not been published., Methods: To evaluate the therapeutic potential of MSCs in the treatment of steroid-refractory acute GvHD, we conducted a systematic literature search. We included all studies that focused on MSC treatment of adult allogeneic hematopoietic stem cell transplantation recipients with grades III to IV steroid-refractory acute GvHD and were transparent about their methods and patient selection criteria., Results: From a total of 255 articles, 9 articles met the quality criteria for this study. The proportion of patients achieving complete resolution of all symptoms (complete response, CR) varied between 8% and 83%. Four of the 9 studies reported CR rates above 50%. The GvHD grade at the time of treatment was identified as a predictor of clinical response. Interestingly, complete response but not partial response to MSCs was associated with overall survival. No serious side effects of MSC therapy were reported., Conclusions: MSC treatment does improve the outcome in steroid-refractory acute GvHD patients but well-designed, prospective randomized clinical trials are needed to confirm the potential of MSCs as salvage therapy for steroid-refractory GvHD and to identify those patients that will benefit most.

Objective: To study whether immune status prior to HIV seroconversion predicts CD4 T cell decline during HIV infection., Design: Prospective cohort study including 51 injecting drug users (IDU) who were HIV negative at study entry and seroconverted for HIV during follow-up., Methods: Cryopreserved peripheral blood mononuclear cells obtained before HIV seroconversion were used to measure naive (CD45RO-CD27+), memory (CD45RO+CD27+), and total CD4 T cell numbers, the fraction of dividing Ki67+CD4+ T cells, and CD4 T cell receptor excision circles (TREC). The effect of pre-seroconversion immune status, as defined by these markers, on the rate of CD4 T cell decline during HIV infection was assessed using linear regression for repeated measurements., Results: IDU with low pre-seroconversion CD4 T cell TREC contents lost CD4 T cells at a significantly faster rate during HIV infection than those with a high CD4 T cell TREC content. IDU with higher pre-seroconversion CD4 T cell numbers had a significantly steeper CD4 T cell decline in the first 3 months of HIV infection, but their CD4 T cell counts remained higher throughout HIV infection. Intermediate levels of pre-seroconversion dividing Ki67+CD4+ T cells were associated with a significantly steeper CD4 cell decline than high levels. IDU with the highest pre-seroconversion drug-injecting frequencies showed slower CD4 T cell decline than those who injected less. No correlation was present between pre-seroconversion immune markers and the pre-seroconversion duration or intensity of drug use., Conclusion: Among IDU, immune status prior to HIV infection as measured by TREC content affects the disease course after HIV seroconversion.

Background: HIV-1 infection is characterized by chronic generalized CD8 and CD4 T cell hyperactivation, the biological effect of which is not understood., Objective: To study the relation between chronic immune activation and CD4 T cell depletion in HIV-1 infection., Design: Prospective cohort study among participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS who have a known seroconversion date (n = 102)., Methods: CD4 and CD8 T cell activation marker expression was analysed by FACScan before and after seroconversion (1 and 5 years after seroconversion); T cell proliferation and T cell numbers were also measured. Cox proportional hazard analyses were used to study the predictive value of these parameters for progression to AIDS., Results: Preseroconversion low CD4 T cell numbers or elevated levels of CD4 T cell activation were associated with increased risk for development of AIDS after HIV-1 seroconversion. Progression to AIDS was associated with loss of both CD4 and CD8 naive T cells. The predictive value of CD8 T cell activation was confirmed and, in addition, in the course of infection low CD4 T cell counts and increasing proportions of dividing CD4 T cells, dividing CD8 T cells or elevated CD4 T cell activation marker expression became independent predictors of progression to AIDS., Conclusions: Increased T cell activation has predictive value for HIV-1 disease progression even before seroconversion. These data support the hypothesis that persistent hyperactivation of the immune system may lead to erosion of the naive T cell pool and CD4 T cell depletion.

Objective: Using SCID-Hu mice models and in vitro culture systems, it has been shown that syncytium inducing/CXCR4 using (X4) HIV-1 variants affect thymic function through infection and killing of CXCR4 thymocytes. The effect of X4-emergence on naive, memory and effector T-cell subset kinetics in vivo is, however, not known., Design: Prospective cohort study., Methods: Analysis of changes in naive, memory and effector CD4 and CD8 T-cell numbers and cell division before and after the emergence of X4 variants., Results: Significantly lower numbers of CD4 T cells in patients with X4 variants (n = 18) compared to patients with non-syncytium inducing/CCR5 using variants (n = 74) were due to increased loss of naive and CD27 memory CD4 T cells. In addition, emergence of X4 variants was associated with a small but significant decline in naive CD8 T-cell numbers and increased proportions of dividing CD4 and CD8 naive, memory and effector T cells., Conclusion: Loss of naive T cells may suggest thymic dysfunction, however, such an effect would explain only part of the accelerated naive CD4 T-cell decline because of the longevity of naive T cells. Our data suggest that the accelerated naive CD4 T-cell decline induced by X4 variants is caused mainly by increased death and recruitment to the memory compartment of these cells.

We studied T cell dynamics in four patients who initially responded well to highly active antiretroviral therapy (HAART) but subsequently experienced virological failure. Maintenance of peripheral blood CD4T cell counts was associated with low levels of immune activation. Low reactivity to rebounding virus may preserve normal T lymphocyte distribution over blood and tissues and be associated with stable peripheral blood T cell numbers in virological failures to HAART.